The majority of infections occur via mucosal surfaces, either through breaks in the mucosal barrier or through a pathogens' ability to evade the "front lines" of mucosal defense, the innate immune barrier defenses. Innate defenses prevent the majority of bacteria from damaging or crossing the mucosa, and are integral in signaling the host when this barrier has been breached. Antimicrobial peptides are important components of the mucosal barrier defense. In the small intestinal crypts, highly secretory Paneth cells are the primary source of antimicrobial peptides. These peptides have demonstrated broad-spectrum antibiotic activity in vitro, however their in vivo role is unclear. Using Salmonella enterica serovar Typhimurium as a model pathogen we will study Paneth cell antimicrobial peptide (PCAMP) response to bacterial infection and the impact of this response on the innate protection of the host. We have found that oral wild type S. typhimurium infection of the mouse results in persistent bacterial colonization of the small intestine, decreased expression and production of PCAMP, and alteration of the commensal microbiota. We hypothesize that Paneth cell antimicrobial peptide (PCAMP) expression can be down regulated by bacterial infection, and that the subsequent decreases in PCAMP result in changes in the composition of the commensal microbiota and prolonged pathogen colonization. Aim 1 will focus on the mechanisms of PCAMP regulation, using specific Salmonella mutants to identify the involvement of host signaling pathways. Aim 2 will focus on the biological implications of PCAMP reduction with respect to persistent pathogen colonization and impact on the commensal microbiota. The proposed studies should provide greater understanding of the mechanism of PCAMP regulation, the role of PCAMP in innate mucosal host defense, and the interplay between host and pathogen that determine the balance between successful pathogenesis and host survival.